INTRODUCTION

Iron deficiency and iron-deficiency anemia (IDA) are major health problems worldwide, contributing to the global disease burden. Body iron levels will decline if the iron intake is insufficient to fulfill the needs or to compensate for the physiological or pathological losses of the iron body.¹ Iron deficiency commonly occurs among children under five years old and women of reproductive age (particularly during pregnancy) in low- and middle-income countries, such as Indonesia.² Globally, iron deficiency is the primary cause of nutrition-deficient anemia (i.e., the IDA).³ The World Health Organization (WHO) reported in 2019 that approximately 30% of pre-menopausal women and 40% of under five-year-old children are anemic. The predominant cause was presumed to be iron deficiency.⁴ The IDA is associated with much-reduced health status and quality of life of those patients, denoting that diagnosis and management of IDA are urgently required.⁴

Clinical diagnosis and management of IDA are relatively straightforward, particularly in uncomplicated cases. The diagnosis is confirmed based on the established laboratory tests (Table 1).^3,5 The administration of iron supplementation, either orally or per injection, would effectively rescue those individuals from IDA.^3,6–8 However, population-level approaches would be required to control IDA in endemic areas, including in Indonesia.⁹ Thorough understanding and management would create and execute population-level approaches that effectively reduce the prevalence of IDA. Therefore, this narrative review discussed the pathophysiology and treatment of iron-deficiency anemia and reviewed the current population-level programs in Indonesia to minimize the rate and impact of IDA.

Global epidemiology and clinical presentation of iron deficiency

The WHO estimated in 2019 that approximately 39.8% of children aged 6–59 months old and 29.9% of women aged 15–49 years old were anemic worldwide.⁴ It is well recognized that nutritional deficiencies, particularly iron, are the most common cause of anemia.¹⁰ The Global Burden of Disease Study 2019 also reported that iron deficiency caused 1.1% of disability-adjusted life years across all ages.¹¹

Iron-deficient individuals could be asymptomatic or symptomatic, as well as in the absence or presence of anemia. Clinical signs and symptoms of iron deficiency could include fatigue and lethargy, decreased concentration, dizziness, headache, tinnitus, pica, restless leg syndrome, pallor, alopecia, dry hair or skin, koilonychia, or atrophic glossitis.^1,12,13 Among children with iron deficiency, the symptoms could include irritability and poor feeding.¹⁴ The IDA could exacerbate the clinical presentations of existing medical conditions, including heart disease, and worsen their prognosis as well.¹ Furthermore, IDA would cause substantial medical and social impacts globally, ranging from the adverse outcomes of pregnancy for both mothers and newborns, cognitive impairment in children, learning disabilities, declined physical capabilities in adults, and cognitive reduction in older adults.^15–18 Thus, it is prudent to understand the mechanism of iron homeostasis within the human body and prevent iron deficiency.

Iron homeostasis and its pathophysiology

Iron is crucial for various cellular functions, including DNA synthesis and repair, neurotransmitter production and function, enzymatic activity, and mitochondrial function.¹⁹ However, the excess of cellular iron is toxic as it produces reactive oxygen species. Thus, the iron balance is tightly regulated by reutilizing the body iron (i.e., iron scavenged from senescent erythrocytes by reticuloendothelial macrophages) and limiting the environmental intake (i.e., iron absorbed from diet).²⁰ The iron recycling by reticuloendothelial macrophages contributes to body iron.¹³ A smaller proportion of body iron comes from dietary iron intake, either as heme iron in animal products (which is efficiently absorbed and less susceptible to modulation by other dietary compounds) and non-heme iron in plants (which is less efficient to be absorbed and susceptible to the inhibitory presence of phytates, calcium, or tannins).¹ Of note, absorption of non-heme iron can be enhanced by the intake of meat, ascorbic acid, and citric acid.^21,22 The systemic iron homeostasis is controlled by hepcidin, a peptide hormone primarily synthesized in the liver. The iron content is maintained at around 40 mg/kg and 50 mg/kg in women and men, respectively.²³ Briefly, hepcidin negatively regulates the iron mobilization from macrophages and hepatocytes as well as the iron absorption by duodenal enterocytes through its interaction with ferroportin, a cellular iron-export protein. The iron channel would be occluded upon binding, and the iron-loaded ferroportin would be degraded, inhibiting iron efflux into the blood plasma.^24,25

The cellular iron is primarily stored within hemoglobin (Hb) of erythrocytes (2,500 mg), enzymes (150 mg), and myoglobin (130 mg), with its surplus is stored in the liver.¹ Ferritin is the cellular storage protein for iron, in which the serum ferritin concentration correlates well with total-body iron stores. The measurement of serum ferritin is therefore commonly performed to diagnose disorders of iron metabolism.²³ In addition, approximately 0.1% of total-body iron within the plasma is bound to transferrin, which functions to relocate iron from enterocytes to tissues through its interaction with the transferrin receptor.¹

Iron deficiency could be distinguished into functional and absolute iron deficiencies. The former condition occurs during inflammation as the elevated levels of hepcidin, and the declined transcription of ferroportin would restrict iron efflux into the plasma.^1,26 The latter condition is due to the imbalance between body iron’s “supply and demand.” This could be due to inadequate dietary iron intake, reduced iron absorption (“the supply”), blood loss, increased iron requirements (“the demand”), or both, as summarized in Table 2.